Trial Outcomes & Findings for Hydrocortisone Replacement in Patients With Secondary Adrenal Insufficiency (SUPREME CORT) (NCT NCT01546922)

Last Updated: 2014-07-14

Results Overview

Cognitive domains to be tested: memory, executive functioning, attention and social cognition. The psychological tests consist of oral and written questions or computer tasks. Data is given as Z-scores based on normative data. Higher Z-scores represent a better performance.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

63 participants

Primary outcome timeframe

After completion of treatment period 1 (that is after 10 weeks from baseline) and after treatment period 2 (that is after 20 weeks from baseline).

Results posted on

2014-07-14

Participant Flow

Sixty-three patients were included in the study. Three patients withdrew from the study during the run-in phase, therefore a total of 60 patients started the first treatment period.

Participant milestones

Participant milestones
Measure	First a Low Dose of HC Followed by a High Dose of HC First low dose of hydrocortisone = 0.2-0.3 mg/kg body weight for 10 weeks followed by a high dose of hydrocortisone = 0.4-0.6 mg/kg body weight	First a High Dose of HC Followed by a Low Dose of HC First high dose of hydrocortisone = 0.4-0.6 mg/kg body weight for 10 weeks followed by a low dose of hydrocortisone = 0.2-0.3 mg/kg body weight
First Period of 10 Weeks STARTED	30	30
First Period of 10 Weeks COMPLETED	25	28
First Period of 10 Weeks NOT COMPLETED	5	2
Second Period of 10 Weeks STARTED	25	28
Second Period of 10 Weeks COMPLETED	22	25
Second Period of 10 Weeks NOT COMPLETED	3	3

Reasons for withdrawal

Reasons for withdrawal
Measure	First a Low Dose of HC Followed by a High Dose of HC First low dose of hydrocortisone = 0.2-0.3 mg/kg body weight for 10 weeks followed by a high dose of hydrocortisone = 0.4-0.6 mg/kg body weight	First a High Dose of HC Followed by a Low Dose of HC First high dose of hydrocortisone = 0.4-0.6 mg/kg body weight for 10 weeks followed by a low dose of hydrocortisone = 0.2-0.3 mg/kg body weight
First Period of 10 Weeks Protocol Violation	3	1
First Period of 10 Weeks Withdrawal by Subject	1	1
First Period of 10 Weeks Investigator's judgment	1	0
Second Period of 10 Weeks Protocol Violation	3	1
Second Period of 10 Weeks Withdrawal by Subject	0	2

Baseline Characteristics

Hydrocortisone Replacement in Patients With Secondary Adrenal Insufficiency (SUPREME CORT)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=47 Participants All participants completing both study periods
Age, Continuous	55 years INTER_QUARTILE_RANGE 14 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants
Sex: Female, Male Male	29 Participants n=5 Participants
Region of Enrollment Netherlands	47 participants n=5 Participants
Age at diagnosis	31 years INTER_QUARTILE_RANGE 16 • n=5 Participants
Childhood onset/Adult onset Childhood onset	6 participants n=5 Participants
Childhood onset/Adult onset Adult onset	41 participants n=5 Participants
Body weight	82.5 kilogram INTER_QUARTILE_RANGE 13.9 • n=5 Participants
Type of surgery Transsphenoïdal surgery	23 participants n=5 Participants
Type of surgery Craniotomy	9 participants n=5 Participants
Age at surgery	39 years n=5 Participants
Median time since surgery	11 years n=5 Participants
Patients with a second surgery	5 participants n=5 Participants
Type of radiotherapy Pituitary radiotherapy	16 participants n=5 Participants
Type of radiotherapy Cranial irradiation	2 participants n=5 Participants
Type of radiotherapy Radiotherapy for extracranial tumors	1 participants n=5 Participants
Age at radiotherapy	43 years n=5 Participants
Median time since radiotherapy	12 years n=5 Participants
Total daily dose hydrocortisone treatment prior to randomization	25 mg/day n=5 Participants
Dose per kg body weight prior to randomization	0.32 mg/kg body weight n=5 Participants
Number of daily dosings prior to randomization 1 dose per day	3 participants n=5 Participants
Number of daily dosings prior to randomization 2 doses per day	33 participants n=5 Participants
Number of daily dosings prior to randomization 3 doses per day	11 participants n=5 Participants
Duration of hydrocortisone treatment prior to randomization	12 years n=5 Participants
Number of hormonal replacements 1 hormonal replacement	3 participants n=5 Participants
Number of hormonal replacements 2 hormonal replacements	9 participants n=5 Participants
Number of hormonal replacements 3 hormonal replacements	21 participants n=5 Participants
Number of hormonal replacements 4 hormonal replacements	11 participants n=5 Participants
Number of hormonal replacements 5 hormonal replacements	3 participants n=5 Participants
Thyroid hormone substitution	43 participants n=5 Participants
Growth hormone (GH) Participants substituted	21 participants n=5 Participants
Growth hormone (GH) Participants unsubstituted	10 participants n=5 Participants
Sex hormone Participants substituted	27 participants n=5 Participants
Sex hormone Men: testosterone substitution	23 participants n=5 Participants
Sex hormone Premenopausal women: estrogen substitution	4 participants n=5 Participants
Desmopressin substitution	9 participants n=5 Participants

PRIMARY outcome

Timeframe: After completion of treatment period 1 (that is after 10 weeks from baseline) and after treatment period 2 (that is after 20 weeks from baseline).

Population: The participants completing both study periods were analyzed

Outcome measures

SECONDARY outcome

Timeframe: After completion of treatment period 1 (that is after 10 weeks from baseline) and after treatment period 2 (that is after 20 weeks from baseline).

Quality of life questionnaires have to be filled in by the participant at his/her home place and have to be returned by post.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After completion of treatment period 1 (that is after 10 weeks from baseline) and after treatment period 2 (that is after 20 weeks from baseline).

Cardiovascular and metabolic risk factors, (pituitary) hormones and bone markers.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After completion of treatment period 1 (that is after 10 weeks from baseline) and after treatment period 2 (that is after 20 weeks from baseline).

Measures of somatosensation: the mechanical detection threshold, the mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, wind up ratio and the pressure pain threshold.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: during treatment period 1 (that is from week 1 to week 10 from baseline) and during treatment period 2 (that is from week 11 to week 20 from baseline).

The patients report common somatic complaints by filling in structured daily diaries.

Outcome measures

Outcome data not reported

Adverse Events

Low Dose of HC

Serious events: 1 serious events

Other events: 20 other events

Deaths: 0 deaths

High Dose of HC

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Low Dose of HC n=58 participants at risk Administration of a low dose of hydrocortisone (0.2-0.3 mg/kg body weight) for 10 weeks	High Dose of HC n=55 participants at risk Administration of a high dose of hydrocortisone (0.4-0.6 mg/kg body weight) for 10 weeks
Infections and infestations Influenza A infection	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Vascular disorders Minor stroke left cerebral hemisphere	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.

Other adverse events

Additional Information

A. P. van Beek, MD PhD

University Medical Center Groningen

Phone: 00315036110388

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Low Dose of Hydrocortisone n=47 Participants Results from the participants while receiving the low dose of hydrocortisone	High Dose of Hydrocortisone n=47 Participants Results from the participants while receiving the high dose of hydrocortisone
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. RBMT-Immediate Memory	-0.41 Z-scores based on normative data. Standard Deviation 0.95	-0.42 Z-scores based on normative data. Standard Deviation 1.33
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. RBMT-Delayed Memory	0.07 Z-scores based on normative data. Standard Deviation 0.98	0.10 Z-scores based on normative data. Standard Deviation 1.33
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. RBMT-Delayed corrected for immediate memory	0.85 Z-scores based on normative data. Standard Deviation 1.09	0.89 Z-scores based on normative data. Standard Deviation 1.34
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. 15 Words Test-Short-term memory	0.36 Z-scores based on normative data. Standard Deviation 1.01	-0.03 Z-scores based on normative data. Standard Deviation 1.03
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. 15 Words Test-Total immediate memory	0.43 Z-scores based on normative data. Standard Deviation 1.02	0.25 Z-scores based on normative data. Standard Deviation 0.92
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. 15 Words Test - Learning Score	0.08 Z-scores based on normative data. Standard Deviation 1.05	0.38 Z-scores based on normative data. Standard Deviation 1.19
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. 15 Words Test - Delayed Memory	0.02 Z-scores based on normative data. Standard Deviation 1.04	0.23 Z-scores based on normative data. Standard Deviation 0.97
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. 15 Words Test - Delayed corrected for total memory	-0.30 Z-scores based on normative data. Standard Deviation 0.99	-0.16 Z-scores based on normative data. Standard Deviation 0.99
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. 15 Words Test-Recognition	-0.11 Z-scores based on normative data. Standard Deviation 0.88	0.08 Z-scores based on normative data. Standard Deviation 0.71
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Digit Span forward - Short term memory	0.49 Z-scores based on normative data. Standard Deviation 0.97	0.56 Z-scores based on normative data. Standard Deviation 0.97
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Rey Complex Figure - Immediate memory	1.14 Z-scores based on normative data. Standard Deviation 1.26	1.40 Z-scores based on normative data. Standard Deviation 1.29
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Rey Complex Figure - Delayed memory	1.11 Z-scores based on normative data. Standard Deviation 1.22	1.28 Z-scores based on normative data. Standard Deviation 1.29
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Divided attention-reaction time auditory response	-0.87 Z-scores based on normative data. Standard Deviation 0.81	-0.89 Z-scores based on normative data. Standard Deviation 0.82
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Divided attention-reaction time visual response	-0.06 Z-scores based on normative data. Standard Deviation 1.00	0.03 Z-scores based on normative data. Standard Deviation 0.94
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Divided attention - Number of omission errors	-0.02 Z-scores based on normative data. Standard Deviation 0.86	-0.14 Z-scores based on normative data. Standard Deviation 0.93
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Divided attention - Number of commission errors	0.30 Z-scores based on normative data. Standard Deviation 1.01	0.34 Z-scores based on normative data. Standard Deviation 0.76
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Visual scanning - Reaction time for target stimuli	-0.38 Z-scores based on normative data. Standard Deviation 1.04	-0.36 Z-scores based on normative data. Standard Deviation 1.03
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Visual scanning - Number of omission errors	-0.03 Z-scores based on normative data. Standard Deviation 1.06	0.08 Z-scores based on normative data. Standard Deviation 1.08
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Visual scanning - Number of commission errors	-0.72 Z-scores based on normative data. Standard Deviation 0.26	-0.70 Z-scores based on normative data. Standard Deviation 0.28
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Alertness - Reaction time tonic alertness	-0.90 Z-scores based on normative data. Standard Deviation 0.73	-0.99 Z-scores based on normative data. Standard Deviation 0.73
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Alertness - Reaction time phasic alertness	-1.03 Z-scores based on normative data. Standard Deviation 0.67	-1.10 Z-scores based on normative data. Standard Deviation 0.66
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Semantic fluency	0.02 Z-scores based on normative data. Standard Deviation 1.24	0.09 Z-scores based on normative data. Standard Deviation 1.18
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Phonemic fluency	0.32 Z-scores based on normative data. Standard Deviation 1.48	0.21 Z-scores based on normative data. Standard Deviation 1.31
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Digit Span backwards-Working memory	0.05 Z-scores based on normative data. Standard Deviation 0.86	-0.01 Z-scores based on normative data. Standard Deviation 1.02
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Trail Making Test - Time condition A	-0.32 Z-scores based on normative data. Standard Deviation 1.14	-0.26 Z-scores based on normative data. Standard Deviation 1.06
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Trail Making Test - Time condition B	0.16 Z-scores based on normative data. Standard Deviation 1.46	0.18 Z-scores based on normative data. Standard Deviation 1.31
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Trail Making Test - Condition B/A	0.37 Z-scores based on normative data. Standard Deviation 1.42	0.36 Z-scores based on normative data. Standard Deviation 1.48
Change in Cognition After 10 Weeks of Treatment With a Low Dose of Hydrocortisone Compared to 10 Weeks of Treatment With a High Dose of Hydrocortisone. Social Cognition	-0.67 Z-scores based on normative data. Standard Deviation 1.20	-0.71 Z-scores based on normative data. Standard Deviation 1.15

Measure	Low Dose of HC n=58 participants at risk Administration of a low dose of hydrocortisone (0.2-0.3 mg/kg body weight) for 10 weeks	High Dose of HC n=55 participants at risk Administration of a high dose of hydrocortisone (0.4-0.6 mg/kg body weight) for 10 weeks
Infections and infestations Influenza	3.4% 2/58 • Number of events 2 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Skin and subcutaneous tissue disorders Rash	3.4% 2/58 • Number of events 2 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
General disorders Tiredness	5.2% 3/58 • Number of events 3 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Musculoskeletal and connective tissue disorders Joint pain	3.4% 2/58 • Number of events 2 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	3.6% 2/55 • Number of events 2 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Immune system disorders Allergic reaction to Ibuprofen	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Psychiatric disorders Progressive depression	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
General disorders Dizziness	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
General disorders Headache	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Renal and urinary disorders Cystitis	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
General disorders Stiffness in joints	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Gastrointestinal disorders Gasteroenteritis	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Cardiac disorders Cardiac catheterisation	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Nervous system disorders Sciatica	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Skin and subcutaneous tissue disorders Herpes Zoster	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
General disorders Nausea	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Injury, poisoning and procedural complications Broken arm	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Injury, poisoning and procedural complications Motorcycle accident	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Skin and subcutaneous tissue disorders Red spots in face	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Eye disorders Diplopia with operative correction	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Skin and subcutaneous tissue disorders Acne on back and forehead	1.7% 1/58 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	0.00% 0/55 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.
Injury, poisoning and procedural complications Fall from a horse	0.00% 0/58 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.	1.8% 1/55 • Number of events 1 • 4 weeks run in phase (if applicable) + 10 weeks (treatment period 1) + 10 weeks (treatment period 2) On testdays patients were questioned to report any adverse events. Furthermore, in week 5 and week 15 of the treatment period, patients were asked if any adverse events happened. In between these assessments patients were able to report any adverse events when necessary.